Differential pharmacology and clinical utility of dapagliflozin in type 2 diabetes

Figures & data

Table 1 Pharmacokinetic characteristics of currently approved SGLT2 inhibitors

	Dapagliflozin	Empagliflozin	Canagliflozin	Ertugliflozin
Absorption (Tmax)	2 hours	1.5 hours	1–2 hours	1 hour
Bioavailability	78%	78%	65%	100%
Fraction bound to protein	91%	86%	99%	93.6%
Volume of distribution	118 L	73.8 L	83.5 L	86 L
T1/2	12.9 hours	12.4 hours	13.1 hours	17 hours
SGLT2 inhibition IC50	1.2 nM	3.1 nM	2.7 nM	0.9 nM
SGLT1 inhibition IC50	1400 nM	8300 nM	710 nM	1960 nM
Metabolism	Glucuronidation	Glucuronidation	Glucuronidation	Glucuronidation
Elimination route	21% feces 75% urine	41% feces 54% urine	52% feces 33% urine	41% feces 50% urine

Abbreviations: SGLT2, sodium-glucose cotransporter 2; T1/2, drug half-life; IC₅₀, the concentration needed to achieve 50% of inhibition.

Table 2 Effects of dapagliflozin on anthropometric and metabolic variables in patients with type 2 diabetes

Study	N	Duration	Carbohydrate variables	Anthropometric variables and blood pressure
Dapagliflozin in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs^Citation93 (placebo-subtracted differences)	272	24 weeks	HbA1c (%): −0.84, P<0.0001 FBG (mg/dL): −30.69, P<0.0001 TDDI (IU): −1.43, P<0.001	Weight (kg): mean group difference): −1.38, P<0.0001 SBP (mmHg): −5.1 mmHg
Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes^Citation94 (dapagliflozin vs dapagliflozin plus saxagliptin vs glimepiride)	939	52 weeks	HbA1c (%): −0.82 vs −1.20 vs −0.9 (drug combination vs glimepiride P<0.01) FBG (mmol/L) −1.6 vs −2.1 vs −1.5 (combination vs glimepiride P<0.01)	Weight (kg): −3.5 vs −3.2 vs +1.8 (both P<0.001 vs glimepiride) Blood pressure (mmHg): -5.6 vs −6.4 vs −1.6 (both P<0.001 vs glimepiride)
Efficacy and safety of dapagliflozin in T2DM patients with chronic kidney disease stage 3A: The DERIVE Study^Citation40 (dapagliflozin vs placebo)	321	24 weeks	HbA1c (%): −0.37 vs −0.03, P<0.001 FPG (mmol/L): −1.2 vs −0.3 mmol/L, P=0.001	Weight (kg): −3.17 vs −1.92, P<0.001 SBP (mmHg): −4.8 vs −1.7, P<0.05
Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1) ^Citation43 (placebo-subtracted differences)	833	24 weeks	HbA1c (%): –0.42, P<0.0001 with dapagliflozin 5 mg and –0.45, P<0.0001 with dapagliflozin 10 mg Mean change in TDDI (IU): –8·80 with dapagliflozin 5 mg and –13.17 with dapagliflozin 10 mg (both P<0.0001) CGM (mg/dL): −15·3 with dapagliflozin 5 mg and −18.0 with dapagliflozin 10 mg (both P<0.001)	Weight (Kg): –2.96 with dapagliflozin 5 mg and –3.72 with dapagliflozin 10 mg (both P<0.0001)
Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study)^Citation44 (placebo-subtracted differences)	843	24 weeks	HbA1c (%): −0.37 with dapagliflozin 5 mg and −0.42 with dapagliflozin 10 mg (both P<0.0001) Mean change in TDDI (IU): −10.78 with dapagliflozin 5 mg and −11.08 with dapagliflozin 10 mg (both P<0.0001) CGM (mg/dl): −15.66 with dapagliflozin 5 mg and −19.74 with dapagliflozin 10 mg (both P<0.01)	Weight(kg): −3.21 with dapagliflozin 5 mg and −3.74 with dapagliflozin 10 mg (both P<0.0001)
Dapagliflozin in the treatment of patients with type 2 diabetes presenting with high baseline A1C^Citation39 (dapagliflozin 5mg vs dapagliflozin 10mg vs placebo)		24 weeks	HbA1c (%): Baseline >/=9%: −1.37 vs −1.39 vs −0.65 (both P<0.0001 Baseline >/=10%: −2.13 vs −1.59 vs −0.82 (both P<0.0001)	Reductions in body weight >5%: −15.7% vs −18.9% vs −3.6% (both P<0.001)
Dapagliflozin and cardiovascular outcomes in type 2 diabetes - DECLARE–TIMI 58^Citation52 (dapagliflozin vs placebo)	17,160	4.2 years	HbA1c (%): −0.42

Abbreviations: HbA1c, glycated hemoglobin; FBG, fasting plasma glucose; CGM, continuous glucose monitoring; T2DM, type 2 diabetes mellitus; TDDI, total daily dose of Insulin.

Table 3 Effects of dapaliflozin on renal function and cardiovascular events in large prospective trials and meta-analyses

Pooled analysis of 11 phase 3 studies with 10 mg dapagliflozin vs placebo^Citation95 (N=4404, duration: 24 weeks)	Dapagliflozin decreased albumin excretion in patients with baseline albuminuria regardless of eGFR (P<0.001)
CVD-REAL study^Citation49 (309,056 patients received for 4 years either SGLT2 inhibitor or other glucose-lowering drugs. Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT2 inhibitor class)	lower rate of HHF (HR: 0.61; 95%CI: 0.51–0.73, P<0.001) lower rate of CV death (HR: 0.49; 95%CI: 0.41–0.57, P<0.01)
DECLARE-TIMI 58^Citation52 (17,160 patients with T2DM, of whom 10,186 without atherosclerotic cardiovascular disease, received 10 mg of dapagliflozin daily or matching placebo for 4.2 years)	Primary outcomes dapagliflozin was noninferior to placebo with respect to the primary safety outcome of MACE dapagliflozin did not result in a significantly lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR: 0.93; 95%CI: 0.84–1.03, P=0.17) dapagliflozin was associated with a lower rate of CV death or HHF (4.9% vs 5.8%; HR: 0.83; 95%CI: 0.73–0.95, P=0.005) Secondary outcomes dapagliflozin was associated with a lower rate of adverse renal outcomes (HR: 0.76; 95%CI: 0.67–0.87)

Abbreviations: SGLT2, sodium-glucose cotransporter 2; HHF, hospitalization for heart failure; CVD, cardiovascular disease; T2DM, type 2 diabetes mellitus; MACE, major adverse cardiovascular events.

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